Devices and methods for tissue engineering

ABSTRACT

A resorbable tissue scaffold fabricated from bioactive glass fiber forms a rigid three-dimensional porous matrix having a bioactive composition. Porosity in the form of interconnected pore space is provided by the space between the bioactive glass fiber in the porous matrix. Strength of the bioresorbable matrix is provided by bioactive glass that fuses and bonds the bioactive glass fiber into the rigid three-dimensional matrix. The resorbable tissue scaffold supports tissue in-growth to provide osteoconductivity as a resorbable tissue scaffold, used for the repair of damaged and/or diseased bone tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/180,638 entitled “Devices and Methods for Tissue Engineering” filedFeb. 14, 2014 which claims the benefit of U.S. patent application Ser.No. 12/832,394 filed Jul. 8, 2010 entitled “Devices and Methods forTissue Engineering” which claims the benefit of Provisional ApplicationNo. 61/224,675, filed Jul. 10, 2009 and Provisional Application No.61/234,768, filed Aug. 18, 2009, each of which are incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of porous fibrousmedical implants. More specifically, the invention relates to abioactive fibrous implant having osteostimulative properties inapplications of in vivo environments.

BACKGROUND OF THE INVENTION

Prosthetic devices are often required for repairing defects in bonetissue in surgical and orthopedic procedures. Prostheses areincreasingly required for the replacement or repair of diseased ordeteriorated bone tissue in an aging population and to enhance thebody's own mechanism to produce rapid healing of musculoskeletalinjuries resulting from severe trauma or degenerative disease.

Autografting and allografting procedures have been developed for therepair of bone defects. In autografting procedures, bone grafts areharvested from a donor site in the patient, for example from the iliaccrest, to implant at the repair site, in order to promote regenerationof bone tissue. However, autografting procedures are particularlyinvasive, causing risk of infection and unnecessary pain and discomfortat the harvest site. In allografting procedures, bone grafts are usedfrom a donor of the same species but the use of these materials canraise the risk of infection, disease transmission, and immune reactions,as well as religious objections. Accordingly, synthetic materials andmethods for implanting synthetic materials have been sought as analternative to autografting and allografting.

Synthetic prosthetic devices for the repair of defects in bone tissuehave been developed in an attempt to provide a material with themechanical properties of natural bone materials, while promoting bonetissue growth to provide a durable and permanent repair. Knowledge ofthe structure and bio-mechanical properties of bone, and anunderstanding of the bone healing process provides guidance on desiredproperties and characteristics of an ideal synthetic prosthetic devicefor bone repair. These characteristics include, but are not limited to:bioresorbability so that the device effectively dissolves in the bodywithout harmful side effects; osteostimulation and/or osteoconductivityto promote bone tissue in-growth into the device as the wound heals; andload bearing or weight sharing to support the repair site yet exercisethe tissue as the wound heals to promote a durable repair.

Materials developed to date have been successful in attaining at leastsome of the desired characteristics, but nearly all materials compromiseat least some aspect of the bio-mechanical requirements of an ideal hardtissue scaffold.

BRIEF SUMMARY OF THE INVENTION

The present invention meets the objectives of an effective syntheticbone prosthetic for the repair of bone defects by providing a materialthat is bioresorbable, osteostimulative, and load bearing. The presentinvention provides a bioresorbable (i.e., resorbable) tissue scaffold ofbioactive glass fiber with a bioactive glass bonding at least a portionof the fiber to form a rigid three dimensional porous matrix. The porousmatrix has interconnected pore space with a pore size distribution inthe range of about 10 μm to about 500 μm with porosity between 40% and85% to provide osteoconductivity once implanted in bone tissue.Embodiments of the present invention include pore space having abi-modal pore size distribution.

Methods of fabricating a synthetic bone prosthesis according to thepresent invention are also provided that include mixing bioactive fiberwith volatile components including a pore former, and a liquid toprovide a plastically formable batch, and kneading the formable batch todistribute the bioactive fiber into a substantially homogeneous mass ofintertangled and overlapping bioactive fiber. The formable batch isdried, heated to remove the volatile components and to form bondsbetween the intertangled and overlapping bioactive glass fiber using anexothermic reaction of the pore former. Embodiments of the presentinvention initiate the exothermic reaction during the heating step at atemperature less than the devitrification temperature of the bioactivefiber, and complete the exothermic reaction before the fiber reaches itsdevitrification temperature. Embodiments of the present inventioninitiate the exothermic reaction of the pore former during the heatingstep at a temperature less than the devitrification temperature of thebioactive fiber, and complete the exothermic reaction after the fiberexceeds its devitrification temperature.

These and other features of the present invention will become apparentfrom a reading of the following descriptions and may be realized bymeans of the instrumentalities and combinations particularly pointed outin the appended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

The foregoing and other objects, features, and advantages of theinvention will be apparent from the following detailed description ofthe several embodiments of the invention, as illustrated in theaccompanying drawings in which like reference characters refer to thesame parts throughout the different views. The drawings are notnecessarily to scale, with emphasis instead being placed uponillustrating the principles of the invention.

FIG. 1 is an optical micrograph at approximately 1000× magnificationshowing an embodiment of a bioactive tissue scaffold according to thepresent invention.

FIG. 2 is a flowchart of an embodiment of a method of the presentinvention for forming the bioactive tissue scaffold of FIG. 1.

FIG. 3 is a flowchart of an embodiment of a curing step according to themethod of FIG. 2 invention.

FIG. 4 is a schematic representation of an embodiment of an objectfabricated according at a method of the present invention.

FIG. 5 is a schematic representation of the object of FIG. 4 uponcompletion of a volatile component removal step of the method of thepresent invention.

FIG. 6 is a schematic representation of the object of FIG. 5 uponcompletion of a bond formation step of the method of the presentinvention.

FIG. 7 is a graph of a comparative analysis of various embodiments ofresorbable tissue scaffolds of the present invention compared to knownsamples.

FIG. 8 is a side elevation view of a bioactive tissue scaffold accordingto the present invention manufactured into a spinal implant.

FIG. 9 is a side perspective view of a portion of a spine having thespinal implant of FIG. 8 implanted in the intervertebral space.

FIG. 10 is a schematic drawing showing an isometric view of a bioactivetissue scaffold according to the present invention manufactured into anosteotomy wedge.

FIG. 11 is a schematic drawing showing an exploded view of the osteotomywedge of FIG. 10 operable to be inserted into an osteotomy opening in abone.

FIG. 12 is a graph of a representative thermal profile of the curingstep of embodiments of the method of the present invention.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a synthetic prosthetic tissue scaffoldfor the repair of tissue defects. As used herein, the terms “syntheticprosthetic tissue scaffold” and “bone tissue scaffold” and “tissuescaffold” and “synthetic bone prosthetic” in various forms may be usedinterchangeably throughout. In an embodiment, the synthetic prosthetictissue scaffold is bioresorbable once implanted in living tissue. In anembodiment, the synthetic prosthetic tissue scaffold is osteoconductiveonce implanted in living tissue. In an embodiment, the syntheticprosthetic tissue scaffold is osteostimulative once implanted in livingtissue. In an embodiment, the synthetic prosthetic tissue scaffold isload bearing once implanted in living tissue.

Various types of synthetic implants have been developed for tissueengineering applications in an attempt to provide a synthetic prostheticdevice that mimics the properties of natural bone tissue and promoteshealing and repair of tissue. Metallic and bio-persistent structureshave been developed to provide high strength in a porous structure thatpromotes the growth of new tissue. These materials however, are notbioresorbable and must either be removed in subsequent surgicalprocedures or left inside the body for the life of the patient. Adisadvantage of bio-persistent metallic and biocompatible implants isthat the high load bearing capability does not transfer to regeneratedtissue surrounding the implant. When hard tissue is formed, stressloading results in a stronger tissue but the metallic implant shieldsthe newly formed bone from receiving this stress. Stress shielding ofbone tissue therefore results in weak bone tissue which can actually beresorbed by the body, which is an initiator of prosthesis loosening.

Implants into living tissue evoke a biological response dependent upon anumber of factors, such as the composition of the implant. Biologicallyinactive materials are commonly encapsulated with fibrous tissue toisolate the implant from the host. Metals and most polymers produce thisinterfacial response, as do nearly inert ceramics, such as alumina orzirconia. Biologically active materials or bioactive materials, elicit abiological response that can produce an interfacial bond securing theimplant material to the living tissue, much like the interface that isformed when natural tissue repairs itself. This interfacial bonding canlead to an interface that stabilizes the scaffold or implant in the bonybed and provide stress transfer from the scaffold across the bondedinterface into the bone tissue. When loads are applied to the repair,the bone tissue including the regenerated bone tissue is stressed, thuslimiting bone tissue resorption due to stress shielding. A bioresorbablematerial can elicit the same response as a bioactive material, but canalso exhibit complete chemical degradation by body fluid.

The challenge in developing a resorbable tissue scaffold usingbiologically active and resorbable materials is to attain load bearingstrength with porosity sufficient to promote the growth of bone tissue.Conventional bioactive bioglass and bioceramic materials in a porousform are not known to be inherently strong enough to provideload-bearing strength as a synthetic prosthesis or implant. Conventionalbioactive materials prepared into a tissue scaffold with sufficientporosity to be osteostimulative have not exhibited load bearingstrength. Similarly, conventional bioactive materials in a form thatprovides sufficient strength do not exhibit a pore structure that can beconsidered to be osteostimulative.

Fiber-based structures are generally known to provide inherently higherstrength to weight ratios, given that the strength of an individualfiber can be significantly greater than powder-based or particle-basedmaterials of the same composition. A fiber can be produced withrelatively few discontinuities that contribute to the formation ofstress concentrations for failure propagation. By contrast, apowder-based or particle-based material requires the formation of bondsbetween each of the adjoining particles, with each bond interfacepotentially creating a stress concentration. Furthermore, a fiber-basedstructure provides for stress relief and thus, greater strength, whenthe fiber-based structure is subjected to strain in that the failure ofany one individual fiber does not propagate through adjacent fibers.Accordingly, a fiber-based structure exhibits superior mechanicalstrength properties over an equivalent size and porosity than apowder-based material of the same composition.

Bioactive fiber-based materials have been proposed for tissueengineering applications but these prior art materials compromise eitherthe load bearing requirement or the osteostimulative properties. Forexample, the teachings of Marcolongo et al. (U.S. Pat. No. 5,645,934)disclose a braided bioactive glass fiber composite structure with athermoplastic polymer to provide load bearing capability, butinsufficient porosity to provide osteostimulation. Similarly, theteachings of Dunn et al. (U.S. Pat. No. 4,655,777) discloses a bioactiveglass fiber reinforced bioactive polymer matrix to provide a loadbearing hard tissue scaffold, that relies upon the dissolution of thebioactive polymer to facilitate in-growth of bone tissue as thesurrounding bone heals. The teachings of Pirhonen (U.S. Pat. No.7,241,486) disclose a porous bone filler material prepared by sinteringbioactive glass fibers, but the resulting pore morphology is not wellcontrolled to ensure osteoconductivity and/or osteostimulation whenfabricated in a form having high strength for potentially load bearingapplications.

The present invention provides a material for tissue engineeringapplications that is bioresorbable, with load bearing capability, andosteostimulative with a pore structure that can be controlled andoptimized to promote the in-growth of bone.

FIG. 1 is an optical micrograph at approximately 1000× magnificationshowing an embodiment of a bioactive tissue scaffold 100 of the presentinvention. The bioactive tissue scaffold 100 is a rigidthree-dimensional matrix 110 forming a structure that mimics bonestructure in strength and pore morphology. As used herein, the term“rigid” means the structure does not significantly yield upon theapplication of stress until it fractured in the same way that naturalbone would be considered to be a rigid structure. The scaffold 100 is aporous material having a network of pores 120 that are generallyinterconnected. In an embodiment, the interconnected network of pores120 provide osteoconductivity. As used herein, the term osteoconductivemeans that the material can facilitate the in-growth of bone tissue.Cancellous bone of a typical human has a compressive crush strengthranging between about 4 to about 12 MPa with an elastic modulus rangingbetween about 0.1 to about 0.5 GPa. As will be shown herein below, thebioactive tissue scaffold 100 of the present invention can provide aporous osteostimulative structure in a bioactive material with porositygreater than 50% and compressive crush strength greater than 4 MPa, upto, and exceeding 22 MPa.

In an embodiment, the three dimensional matrix 110 is formed from fibersthat are bonded and fused into a rigid structure, with a compositionthat exhibits bioresorbability. The use of fibers as a raw material forcreating the three dimensional matrix 110 provides a distinct advantageover the use of conventional bioactive or bioresorbable powder-based rawmaterials. In an embodiment, the fiber-based raw material provides astructure that has more strength at a given porosity than a powder-basedstructure. In an embodiment, the use of fibers as the primary rawmaterial results in a bioactive material that exhibits more uniform andcontrolled dissolution rates in body fluid.

In an embodiment, the fiber-based material of the three-dimensionalmatrix 110 exhibits superior bioresorbability characteristics over thesame compositions in a powder-based or particle-based system. Forexample, dissolution rates are increasingly variable and thus,unpredictable, when the material exhibits grain boundaries, such as apowder-based material form, or when the material is in a crystallinephase. Particle-based materials have been shown to exhibit rapiddecrease in strength when dissolved by body fluids, exhibiting failuresdue to fatigue from crack propagation at the particle grain boundaries.Since bioactive glass or ceramic materials in fiber form are generallyamorphous, and the heat treatment processes of the methods of thepresent invention can better control the amount and degree of orderedstructure and crystallinity, the tissue scaffold 100 of the presentinvention can exhibit more controlled dissolution rates, with higherstrength.

The bioactive tissue scaffold 100 of the present invention providesdesired mechanical and chemical characteristics, combined with poremorphology to promote osteoconductivity. The network of pores 120 is thenatural interconnected porosity resulting from the space betweenintertangled, nonwoven fiber material in a structure that mimics thestructure of natural bone. Furthermore, using methods described herein,the pore size can be controlled, and optimized, to enhance the flow ofblood and body fluid within of the scaffold 100 and regenerated bone.For example, pore size and pore size distribution can be controlledthrough the selection of pore formers and organic binders that arevolatized during the formation of the scaffold 100. Pore size and poresize distribution can be determined by the particle size and particlesize distribution of the pore former including a single mode of poresizes, a bi-modal pore size distribution, and/or a multi-modal pore sizedistribution. The porosity of the scaffold 100 can be in the range ofabout 40% to about 85%. In an embodiment, this range promotes theprocess of osteoinduction of the regenerating tissue once implanted inliving tissue while exhibiting load bearing strength.

The scaffold 100 is fabricated using fibers as a raw material. Thefibers can be composed of a bioactive material that exhibitsbioresorbability. The term “fiber” as used herein is meant to describe afilament in a continuous or discontinuous form having an aspect ratiogreater than one, and formed from a fiber-forming process such as drawn,spun, blown, or other similar process typically used in the formation offibrous materials. Bioactive fibers can be fabricated from a bioactivecomposition that is capable of being formed into a fiber form, such asbioactive glasses, ceramics, and glass-ceramics. The fibers can befabricated from precursors of bioactive compositions, that form abioactive composition upon formation of the three-dimensional matrix 110while forming the scaffold 100.

Bioactive and bioresorbable glass materials are generally known as aglass having a composition of sodium carbonate, calcium carbonate,phosphorus pentoxide and silica, such as a glass composition havingabout 45-60 mol % silica and a 2-10 molar ratio of calcium to phosphate.Glass materials having this or a similar composition, demonstrate theformation of a silica-rich layer and a calcium phosphate film on thematerials surface in an aqueous environment that readily bonds the glassmaterial to bone. Compositional variations can be made, through theaddition of compositions such as magnesia, potassium oxide, boric oxide,and other compounds, though it is generally known that a silica contentbetween 45-60 mol % at the interfacial layer is advantageous to theformation of the silica-rich layer with the calcium phosphate film topromote the formation of bonds between the scaffold and the natural bonematerial. For example, see the publication of Ogino, Ohuchi, and Hench,“Compositional Dependence of the Formation of Calcium Phosphate Films onBioglass, J Biomed Mater Res. 1980, 14:55-64 (incorporated herein byreference).

Glass compounds are more easily formed into a fiber form when thematerial can be melted and drawn into a fiber in an amorphous form.Bioactive and bioresorbable materials that can be fabricated into afiber form without devitrification during the fiber drawing processrequire high silica content and both sodium oxide and potassium oxide toprovide a mixed alkali effect to maintain an amorphous structure whenformed into a fiber. Various compounds of mixed alkali and high-silicacontent glasses that can be easily pulled into fibers have demonstratedboth bioactivity and bioresorbability. For example, see the publicationof Brink, Turunen, Happonen, and Yli-Urpo, “Compositional Dependence ofBioactivity of Glasses in the System Na2O—K2O—MgO—CaO—B2O3-P2O5-SiO2,” JBiomed Mater Res. 1997; 37:114-121 (incorporated herein by reference),that describes at least ten different compositions in theNa2O—K2O—MgO—CaO—B2O3-P2O5-SiO2 system that can be readily drawn intofiber and that demonstrate bioactivity. In an embodiment, a bioactiveand bioresorbable material having a composition in respective mol %quantities of 6% Na₂O; 7.9% K₂O; 7.7% MgO; 22.1% CaO; 0% B₂O₃; 1.7%P₂O₅; and 54.6% SiO₂, (also referred to as 13-93 glass) providesbioactive and bioresorbability performance.

Referring still to FIG. 1, the network of pores 120 within thethree-dimensional matrix 110 has a unique structure with properties thatare particularly advantageous for the in-growth of bone tissue as aresorbable scaffold 100. The characteristics of the pore space 120 canbe controlled through the selection of volatile components, as hereindescribed below. Pore size and pore size distribution are importantcharacteristics of the network of pores 120, that can be specified andcontrolled and thus, predetermined through the selection of volatilecomponents having specific particle sizes and distributions to provide astructure that is osteoconductive, while maintaining strength for loadbearing applications. Additionally, the network of pores 120 exhibitsimproved interconnectivity with large relative throat sizes between thepores due to the position of the fibers from the binder and pore formerover the prior art materials that further enhances the osteoconductivityof the resorbable tissue scaffold 100 of the present invention. Thenetwork of pores 120 arises from the space resulting from the naturalpacking density of fibrous materials, and the space resulting fromdisplacement of the fibers by volatile components mixed with the fiberduring the formation of the resorbable scaffold 100. As furtherdescribed below, the bioactive material forming the three dimensionalmatrix 110 is fabricated by fusing and bonding overlapping andintertangled fibers with a glass. The fibers and glass and/or glassprecursors, are non-volatile components that are prepositioned throughthe formation of a homogeneous mixture with volatile components, such asbinders and pore formers, including, for example, organic materials topredetermine the resulting pore size, pore distribution, and throat sizebetween pores. Furthermore, the volatile components effectively increasethe number of pore interconnections by increasing the throat sizebetween pores resulting in pores being connected to multiple pores. Bulkfibers are deagglomerated and distributed throughout the mixture,resulting in a relative positioning of the fibrous materials in anoverlapping and intertangled relationship within the volatile organicmaterials. Upon removal of the volatile components, and fusing andbonding of the fiber and glass to form the three-dimensional matrix 110,the network of pores 120 results from the space occupied by the volatilecomponents.

An objective of a resorbable scaffold of the present invention is tofacilitate in situ tissue generation as an implant within living tissue.While there are many criteria for an ideal scaffold for bone tissuerepair, an important characteristic is a highly interconnected porousnetwork with both pore sizes, and pore interconnections, large enoughfor cell migration, fluid exchange and eventually tissue in-growth andvascularization (e.g., penetration of blood vessels). The resorbabletissue scaffold 100 of the present invention is a porous structure withpore size and pore interconnectivity that is particularly adapted forthe in-growth of bone tissue. The network of pores 120 has a pore sizethat can be controlled through the selection of volatile components usedto fabricate the resorbable tissue scaffold 100, to provide an averagepore size of at least 100 μm. Embodiments of the resorbable tissuescaffold 100 have an average pore size in the range of about 10 μm toabout 600 μm, and alternatively, an average pore size in the range ofabout 100 μm to about 500 μm. The volatile components, including organicbinder and pore formers, that form the pores, ensure a high degree ofinterconnectivity with large pore throat sizes within thethree-dimensional matrix. It may be desirable to have a pore sizedistribution that is smaller than the pore size that may be determinedthrough in vitro analysis, in that the pore size will increase as thethree dimensional matrix 120 is dissolved and resorbed into the body. Inthis way, the load bearing capabilities of this material is enhancedupon initial implant, with the regenerated bone tissue bearing more ofthe load as it regenerates while the resorbable tissue scaffold 100dissolves into the body.

Referring to FIG. 2, an embodiment of a method 200 of forming thebioactive tissue scaffold 100 is shown. Generally, bulk fibers 210 aremixed with a binder 230 and a liquid 250 to form a plastically moldablematerial, which is then cured to form the bioactive tissue scaffold 100.The curing step 280 selectively removes the volatile elements of themixture, leaving the pore space 120 open and interconnected, andeffectively fuses and bonds the fibers 210 into the rigidthree-dimensional matrix 110.

The bulk fibers 210 can be provided in bulk form, or as chopped fibers.The diameter of the fiber 210 can range from about 1 to about 200 μm andtypically between about 5 to about 100 μm. Fibers 210 of this type aretypically produced with a relatively narrow and controlled distributionof fiber diameters, and fibers of a given diameter may be used, or amixture of fibers having a range of fiber diameters can be used. Thediameter of the fibers 210 will influence the resulting pore size andpore size distribution of the porous structure, as well as the size andthickness of the three-dimensional matrix 110, which will influence notonly the osteoconductivity of the scaffold 100, but also the rate atwhich the scaffold 100 is dissolved by body fluids when implanted inliving tissue and the resulting strength characteristics, includingcompressive strength and elastic modulus.

The binder 230 and the liquid 250, when mixed with the fiber 210, createa plastically formable batch mixture that enables the fibers 210 to beevenly distributed throughout the batch, while providing green strengthto permit the batch material to be formed into the desired shape in thesubsequent forming step 270. An organic binder material can be used asthe binder 230, such as methylcellulose, hydroxypropyl methylcellulose(HPMC), ethylcellulose and combinations thereof. The binder 230 caninclude materials such as polyethylene, polypropylene, polybutene,polystyrene, polyvinyl acetate, polyester, isotactic polypropylene,atactic polypropylene, polysulphone, polyacetal polymers, polymethylmethacrylate, fumaron-indane copolymer, ethylene vinyl acetatecopolymer, styrene-butadiene copolymer, acryl rubber, polyvinyl butyral,inomer resin, epoxy resin, nylon, phenol formaldehyde, phenol furfural,paraffin wax, wax emulsions, microcrystalline wax, celluloses,dextrines, chlorinated hydrocarbons, refined alginates, starches,gelatins, lignins, rubbers, acrylics, bitumens, casein, gums, albumins,proteins, glycols, hydroxyethyl cellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide,polyacrylamides, polyethyterimine, agar, agarose, molasses, dextrines,starch, lignosulfonates, lignin liquor, sodium alginate, gum arabic,xanthan gum, gum tragacanth, gum karaya, locust bean gum, irish moss,scleroglucan, acrylics, and cationic galactomanan, or combinationsthereof. Although several binders 230 are listed above, it will beappreciated that other binders may be used. The binder 230 provides thedesired rheology of the plastic batch material in order to form adesired object and maintaining the relative position of the fibers 210in the mixture while the object is formed, while remaining inert withrespect to the bioactive materials. The physical properties of thebinder 230 will influence the pore size and pore size distribution ofthe pore space 120 of the scaffold 100. Preferably, the binder 230 iscapable of thermal disintegration, or selective dissolution, withoutimpacting the chemical composition of the bioactive components,including the fiber 210.

The fluid 250 is added as needed to attain a desired rheology in theplastic batch material suitable for forming the plastic batch materialinto the desired object in the subsequent forming step 270. Water istypically used, though solvents of various types can be utilized.Rheological measurements can be made during the mixing step 260 toevaluate the plasticity and cohesive strength of the mixture prior tothe forming step 270.

Pore formers 240 can be included in the mixture to enhance the porespace 120 of the bioactive scaffold 100. Pore formers are non-reactivematerials that occupy volume in the plastic batch material during themixing step 260 and the forming step 270. When used, the particle sizeand size distribution of the pore former 240 will influence theresulting pore size and pore size distribution of the pore space 120 ofthe scaffold 100. Particle sizes can typically range between about 25 μmor less to about 450 μm or more, or alternatively, the particle size forthe pore former can be a function of the fibers 210 diameter rangingfrom about 0.1 to about 100 times the diameter of the fibers 210. Thepore former 240 must be readily removable during the curing step 280without significantly disrupting the relative position of thesurrounding fibers 210. In an embodiment of the invention, the poreformer 240 can be removed via pyrolysis or thermal degradation, orvolatization at elevated temperatures during the curing step 280. Forexample, microwax emulsions, phenolic resin particles, flour, starch, orcarbon particles can be included in the mixture as the pore former 240.Other pore formers 240 can include carbon black, activated carbon,graphite flakes, synthetic graphite, wood flour, modified starch,celluloses, coconut shell husks, latex spheres, bird seeds, saw dust,pyrolyzable polymers, poly (alkyl methacrylate), polymethylmethacrylate, polyethyl methacrylate, poly n-butyl methacrylate,polyethers, poly tetrahydrofuran, poly (1,3-dioxolane), poly (alkaleneoxides), polyethylene oxide, polypropylene oxide, methacrylatecopolymers, polyisobutylene, polytrimethylene carbonate, poly ethyleneoxalate, poly beta-propiolactone, poly delta-valerolactone, polyethylenecarbonate, polypropylene carbonate, vinyl toluene/alpha-methylstyrenecopolymer, styrene/alpha-methyl styrene copolymers, and olefin-sulfurdioxide copolymers. Pore formers 240 may be generally defined as organicor inorganic, with the organic typically burning off at a lowertemperature than the inorganic. Although several pore formers 240 arelisted above, it will be appreciated that other pore formers 240 may beused. Pore formers 240 can be, though need not be, fully biocompatiblesince they are removed from the scaffold 100 during processing.

A bonding agent 220 can be included in the mixture to promote strengthand performance of the resulting bioactive scaffold 100. The bondingagent 220 can include powder-based material of the same composition asthe bulk fiber 210, or it can include powder-based material of adifferent composition. As will be explained in further detail below, thebonding agent 220 based additives enhance the bonding strength of theintertangled fibers 210 forming the three-dimensional matrix 110 throughthe formation of bonds between adjacent and intersecting fibers 210. Thebonding agent 220 can be bioactive glass, glass-ceramic, ceramic, orprecursors thereto.

The relative quantities of the respective materials, including the bulkfiber 210, the binder 230, and the liquid 250 depend on the overallporosity desired in the bioactive tissue scaffold 100. For example, toprovide a scaffold 100 having approximately 60% porosity, thenonvolatile components 275, such as the fiber 210, would amount toapproximately 40% of the mixture by volume. The relative quantity ofvolatile components 285, such as the binder 230 and the liquid 250 wouldamount to approximately 60% of the mixture by volume, with the relativequantity of binder to liquid determined by the desired rheology of themixture. Furthermore, to produce a scaffold 100 having porosity enhanceby the pore former 240, the amount of the volatile components 285 isadjusted to include the volatile pore former 240. Similarly, to producea scaffold 100 having strength enhanced by the bonding agent 220, theamount of the nonvolatile components 275 would be adjusted to includethe nonvolatile bonding agent 220. It can be appreciated that therelative quantities of the nonvolatile components 275 and volatilecomponents 285 and the resulting porosity of the scaffold 100 will varyas the material density may vary due to the reaction of the componentsduring the curing step 280. Specific examples are provided herein below.

In the mixing step 260, the fiber 210, the binder 230, the liquid 250,the pore former 240 and/or the bonding agent 220, if included, are mixedinto a homogeneous mass of a plastically deformable and uniform mixture.The mixing step 260 may include dry mixing, wet mixing, shear mixing,and kneading, which can be necessary to evenly distribute the materialinto a homogeneous mass while imparting the requisite shear forces tobreak up and distribute or de-agglomerate the fibers 210 with thenon-fiber materials. The amount of mixing, shearing, and kneading, andduration of such mixing processes depends on the selection of fibers 210and non-fiber materials, along with the selection of the type of mixingequipment used during the mixing step 260, in order to obtain a uniformand consistent distribution of the materials within the mixture, withthe desired rheological properties for forming the object in thesubsequent forming step 270. Mixing can be performed using industrialmixing equipment, such as batch mixers, shear mixers, and/or kneaders.

The forming step 270 forms the mixture from the mixing step 260 into theobject that will become the bioactive tissue scaffold 100. The formingstep 270 can include extrusion, rolling, pressure casting, or shapinginto nearly any desired form in order to provide a roughly shaped objectthat can be cured in the curing step 280 to provide the scaffold 100. Itcan be appreciated that the final dimensions of the scaffold 100 may bedifferent than the formed object at the forming step 270, due toexpected shrinkage of the object during the curing step 280, and furthermachining and final shaping may be necessary to meet specifieddimensional requirements. In an exemplary embodiment to provide samplesfor mechanical and in vitro and in vivo testing, the forming step 270extrudes the mixture into a cylindrical rod using a piston extruderforcing the mixture through a round die.

The object is then cured into the bioactive tissue scaffold 100 in thecuring step 280, as further described in reference to FIG. 3. In theembodiment shown in FIG. 3, the curing step 280 can be performed as thesequence of three phases: a drying step 310; a volatile componentremoval step 320; and a bond formation step 330. In the first phase,drying 310, the formed object is dried by removing the liquid usingslightly elevated temperature heat with or without forced convection togradually remove the liquid. Various methods of heating the object canbe used, including, but not limited to, heated air convection heating,vacuum freeze drying, solvent extraction, microwave orelectromagnetic/radio frequency (RF) drying methods. The liquid withinthe formed object is preferably not removed too rapidly to avoid dryingcracks due to shrinkage. Typically, for aqueous based systems, theformed object can be dried when exposed to temperatures between about90° C. and about 150° C. for a period of about one hour, though theactual drying time may vary due to the size and shape of the object,with larger, more massive objects taking longer to dry. In the case ofmicrowave or RF energy drying, the liquid itself, and/or othercomponents of the object, adsorb the radiated energy to more evenlygenerate heat throughout the material. During the drying step 310,depending on the selection of materials used as the volatile components,the binder 230 can congeal or gel to provide greater green strength toprovide rigidity and strength in the object for subsequent handling.

Once the object is dried, or substantially free of the liquid component250 by the drying step 310, the next phase of the curing step 280proceeds to the volatile component removal step 320. This phase removesthe volatile components (e.g., the binder 230 and the pore former 240)from the object leaving only the non-volatile components that form thethree-dimensional matrix 110 of the tissue scaffold 100. The volatilecomponents can be removed, for example, through pyrolysis or by thermaldegradation, or solvent extraction. The volatile component removal step320 can be further parsed into a sequence of component removal steps,such as a binder burnout step 340 followed by a pore former removal step350, when the volatile components 285 are selected such that thevolatile component removal step 320 can sequentially remove thecomponents. For example, HPMC used as a binder 230 will thermallydecompose at approximately 300° C. A graphite pore former 220 willoxidize into carbon dioxide when heated to approximately 600° C. in thepresence of oxygen. Similarly, flour or starch, when used as a poreformer 220, will thermally decompose at temperatures between about 300°C. and about 600° C. Accordingly, the formed object composed of a binder230 of HPMC and a pore former 220 of graphite particles, can beprocessed in the volatile component removal step 320 by subjecting theobject to a two-step firing schedule to remove the binder 230 and thenthe pore former 220. In this example, the binder burnout step 340 can beperformed at a temperature of at least about 300° C. but less than about600° C. for a period of time. The pore former removal step 350 can thenbe performed by increasing the temperature to at least about 600° C.with the inclusion of oxygen into the heating chamber. Thisthermally-sequenced volatile component removal step 320 provides for acontrolled removal of the volatile components 285 while maintaining therelative position of the non-volatile components 275 in the formedobject.

FIG. 4 depicts a schematic representation of the various components ofthe formed object prior to the volatile component removal step 320. Thefibers 210 are intertangled within a mixture of the binder 230 and thepore former 240. Optionally, the bonding agent 220 can be furtherdistributed in the mixture (not shown for clarity). FIG. 5 depicts aschematic representation of the formed object upon completion of thevolatile component removal step 320. The fibers 210 maintain theirrelative position as determined from the mixture of the fibers 210 withthe volatile components 285 as the volatile components 285 are removed.Upon completion of the removal of the volatile components 285, themechanical strength of the object may be quite fragile, and handling ofthe object in this state should be performed with care. In anembodiment, each phase of the curing step 280 is performed in the sameoven or kiln. In an embodiment, a handling tray is provided upon whichthe object can be processed to minimize handling damage.

FIG. 6 depicts a schematic representation of the formed object uponcompletion of the last step of the curing step 280, bond formation 330.Pore space 120 is created where the binder 230 and the pore former 240were removed, and the fibers 210 are fused and bonded into the threedimensional matrix 110. The characteristics of the volatile components285, including the size of the pore former 240 and/or the distributionof particle sizes of the pore former 240 and/or the relative quantity ofthe binder 230, together cooperate to predetermine the resulting poresize, pore size distribution, and pore interconnectivity of theresulting tissue scaffold 100. The bonding agent 220 and the glass bondsthat form at overlapping nodes 610 and adjacent nodes 620 of the threedimensional matrix 110 provide for structural integrity of the resultingthree-dimensional matrix 110.

To demonstrate the effect of the combination of the features of thepresent invention, a comparative analysis 700 is shown in FIG. 7. Fivecomparative samples (710, 720, 730, 740, and 750) were prepared andanalyzed for compressive strength (in Mpa) and porosity (as apercentage). Sample 710 demonstrates the strength/porosity relationshipfor a powder-based porous structure of 13-93 bioactive glass. The sample710 was prepared from a mixture of 5 grams of 13-93 bioactive glasspowder, with 2 grams of HPMC organic binder, and water to provide aplastic batch, extruded into a 14 mm diameter rod, and sintered into aporous form at a plurality of sintering temperatures. The sample 720 wasprepared from a mixture of 13-93 bioactive glass fiber with 2 grams ofHPMC organic binder, and water to provide a plastic batch, extruded intoa 14 mm diameter rod, and cured into a porous form at a plurality ofbond formation temperatures, as described above with relation to FIG. 3.Both the sample 710 and the sample 720 did not include a pore former240. As described above, the strength/porosity relationship for thefiber-based system of the sample 720 is improved over the powder-basedsample 710. In sample 720, the organic binder, as a volatile component285, positions the fiber with the space between the fibers predeterminedby the volatile component 285 (here, the organic binder 230) to increasethe porosity over a powder-based sample of the same effective strength.

To demonstrate the effect of the addition of a pore former 240, thesample 730 was prepared from a mixture of 13-93 bioactive glass powderwith 2 grams HPMC organic binder and 1.5 grams of PMMA with a particlesize of 100 μm as a pore former 240 and water to provide a plasticbatch, extruded into a 14 mm diameter rod, and cured into a porous format a plurality of sintering temperatures. Sample 740 was prepared from amixture of 5 grams 13-93 bioactive glass fiber with 2 grams HPMC organicbinder and 1.5 grams of PMMA with a particle size of 100 μm as a poreformer 240 and water to provide a plastic batch, extruded into a 14 mmdiameter rod, and cured into a porous form at a plurality of bondformation temperatures. Sample 750 was prepared from a mixture of 5grams 13-93 bioactive glass fiber with 2 grams HPMC organic binder and 7grams of 4015 graphite powder having a distribution of particle sizes ofbetween about 150 to about 425 μm as a pore former 240, but with theaddition of various quantities of 13-93 bioactive glass powder as abonding agent 220, that was cured at a bond formation temperature ofabout 800° C. Again, the fiber based comparative samples 740 and 750exhibit a strength/porosity relationship that exceeds the performance ofthe samples 710 and 730. The pore former 240 and the binder 230cooperate to predetermine the resulting pore size, pore sizedistribution, and pore interconnectivity of the sample, with higherstrength for a given porosity over conventional methods and devices.

Referring back to FIG. 3, the bond formation step 330 converts thenonvolatile components 275, including the bulk fiber 210, into the rigidthree-dimensional matrix 110 of the bioactive tissue scaffold 100 whilemaintaining the pore space 120 created by the removal of the volatilecomponents 275. The bond formation step 330 heats the non-volatilecomponents 275 to a temperature upon which the bulk fibers 210 bond toadjacent and overlapping fibers 210, and for a duration sufficient toform the bonds, without melting the fibers 210, and thereby destroyingthe relative positioning of the non-volatile components 275. The bondformation temperature and duration depends on the chemical compositionof the non-volatile components 275, including the bulk fiber 210. Abioactive glass fiber or powder of a particular composition exhibitssoftening and a capability for plastic deformation without fracture at aglass transition temperature. Glass materials typically have adevitrification temperature upon which the amorphous glass structurecrystallizes. In an embodiment of the invention, the bond formationtemperature in the bond formation step 330 is in the working rangebetween the glass transition temperature and the devitrificationtemperature. For example the bond formation temperature for 13-93bioactive glass composition can be above the glass transitiontemperature of about 606° C. and less than the devitrificationtemperature of about 851° C.

In the bond formation step 330, the formed object is heated to the bondformation temperature resulting in the formation of glass bonds atoverlapping nodes 610 and adjacent nodes 620 of the fiber structure. Thebonds are formed at overlapping nodes 610 and adjacent nodes 620 of thefiber structure through a reaction of the bonding agent 220 that flowsaround the fibers 210, reacting with the fibers 210 to form a glasscoating and/or glass bonds. In the bond formation step 330, the materialof the fibers 210 may participate in a chemical reaction with thebonding agent 220, or the fibers 210 may remain inert with respect to areaction of the bonding agent 220. Further still, the bulk fibers 210may be a mixture of fiber compositions, with a portion, or all of thefibers 210 participating in a reaction forming bonds to create thethree-dimensional matrix 110.

The duration of the bond formation step 330 depends on the temperatureprofile during the bond formation step 330, in that the time at the bondformation temperature of the fibers 210 is limited to a relatively shortduration so that the relative position of the non-volatile components275, including the bulk fibers 210, does not significantly change. Thepore size, pore size distribution, and interconnectivity between thepores in the formed object are determined by the relative position ofthe bulk fibers 210 by the volatile components 285. While the volatilecomponents 285 are likely burned out of the formed object by the timethe bond formation temperature is attained, the relative positioning ofthe fibers 210 and non-volatile components 275 are not significantlyaltered. The formed object will likely undergo slight or minordensification during the bond formation step 330, but the control ofpore size and distribution of pore sizes can be maintained, andtherefore predetermined by selecting a particle size for the pore former240 that is slightly oversize or adjusting the relative quantity of thevolatile components 285 to account for the expected densification.

In an embodiment of the invention, the bonding agent 220 is a bioactiveglass material ground into a fine powder or nano-particle sizes (e.g.,1-100 nanometers). In this embodiment, the small particle sizes reactmore quickly at or near the glass transition temperature of the materialcomposition, and form a glass that covers and bonds the overlappingnodes 610 and adjacent nodes 620 of the fiber structure before the fibermaterial is appreciably affected by the exposure to the temperature ator near its glass transition temperature. In this embodiment, for thebonding agent 220 to be more reactive than the bulk fibers 210, theparticle size can be in the range of 1 to 1000 times smaller than thediameter of the fibers 210, for example, in the range of 10 microns to10 nanometers when using 10 micron diameter bulk fibers 210.Nanoparticle sized powder can be produced by milling bioactive glassmaterial in a milling or comminution process, such as impact milling orattrition milling in a ball mill or media mill.

The temperature profile of the bond formation step 330 can be controlledto control the amount of crystallization and/or minimize thedevitrification of the resulting three-dimensional matrix 110. Asdescribed above, bioactive glass and bioresorbable glass compoundsexhibit more controlled and predictable dissolution rates in livingtissue when the amount of accessible grain boundaries of the materialsis minimized. These bioactive and bioresorbable materials exhibitsuperior performance as a bioactive device due to the amorphousstructure of the material when fabricated into fibers 210, and thecontrolled degree of crystallinity that occurs during the heat treatmentprocessing during the bond formation step 330. Therefore, in anembodiment of the method of the present invention, the temperatureprofile of the bond formation step 330 is adapted to bond the fiberstructure without increasing grain boundaries in the non-volatilematerials 275.

In an embodiment of the method of the present invention, the bondformation temperature exceeds the devitrification temperature of thebulk fibers 210 during the bond formation step 330. Compositions ofbioactive glass can exhibit a narrow working range between its glasstransition temperature and the crystallization temperature. In thisembodiment, the crystallization of the fibers 210 may not be avoided inorder to promote the formation of the bonds between overlapping andadjacent nodes of the fibers 210 in the structure. For example,bioactive glass in the 45S5 composition has an initial glass transitiontemperature of about 550° C. and a devitrification temperature of about580° C. with crystallization temperatures of various phases attemperatures at about 610, about 800, and about 850° C. With such anarrow working range, the formation of a glass bond using the samecomposition as a bonding agent 220 is difficult to perform, and as such,the bond formation temperature may require bond formation temperaturesin excess of about 900° C. to form the glass bonds. In an alternativeembodiment, the bond formation temperature can exceed thecrystallization temperature of the fibers 210, yet still fall within theworking range of the composition of a bioactive glass in a powder formas a bonding agent 220. In this embodiment, the glass fibers 210 of afirst composition may crystallize, with glass bonds of a secondcomposition forming at overlapping and adjacent nodes of the fiberstructure. For example a 13-93 composition in a powder form as a bondingagent 220 can be used with bioactive glass fibers in a 45S5 composition,to form a glass bond above the glass transition temperature of the 13-93composition but less than the devitrification temperature of the 13-93composition but exceeds the devitrification temperature of the 45S5glass fiber composition to form a composite formed object.

In an embodiment of the invention, the temperature profile of the bondformation step 330 is configured to reach a bond formation temperaturequickly and briefly, with rapid cooling to avoid devitrification of theresulting bioactive material. Various heating methods can be utilized toprovide this heating profile, such as forced convection in a kiln,heating the object directly in a flame, laser, or other focused heatingmethods. In this embodiment, the focused heating method is a secondaryheating method that supplements a primary heating method, such as a kilnor oven heating apparatus. The secondary heating method provides thebrief thermal excursion to the bond formation temperature, with a fastrecovery to a temperature less than the glass transition temperature inorder to avoid devitrification of the resulting three-dimensional matrix110.

In an embodiment of the invention, combustion of the pore former 240 canbe used to provide rapid and uniform heating throughout the objectduring the bond formation step 330. In this embodiment, the pore formerremoval step 350 generally occurs during the bond formation step 330.The pore former 240 is a combustible material, such as carbon orgraphite, starch, organics or polymers, such as polymethyl methacrylate,or other material that exothermically oxidizes at elevated temperaturesless than or equal to the devitrification temperature of the bioactiveglass fiber material 210. Generally, the pore former 240 is selectedbased on the temperature at which the material initiates combustion, ascan be determined by thermal analysis, such as ThermogravimetricAnalysis (TGA) or Differential Thermal Analysis (DTA), or a combinationof TGA and DTA, such as a simultaneous DTA/TGA which detects both massloss and thermal response. For example, Table 1 shows the results of aDTA/TGA analysis of various materials to determined the exothermiccombustion point of the material.

TABLE 1 Pore Former Combustion Temperature Activated Carbon 621° C.Graphite Flakes 603° C. HPMC 375° C. PMMA 346° C. Wood Flour 317° C.Corn Starch 292° C.

During the curing step 280, adapted so the pore former removal step 350generally occurs during the bond formation step 330, the pore formercombustion increases the temperature of the formed object substantiallyuniformly and at an increased rate throughout the object. In this waythe desired bond formation temperature can be attained reasonablyquickly. Once the pore former is fully combusted, the internaltemperature of the formed article will decrease because of the thermalgradient between the internal temperature of the formed object resultingfrom the pore former combustion and the temperature of the surroundingenvironment in the kiln or oven. The result is that the thermal profileof the curing process 280 can include a sharp and brief thermalexcursion at or near the devitrification temperature of the bioactivefiber 210.

Referring to FIG. 12, a representative thermal profile of a portion ofthe curing process 280 is shown where the pore former removal step 350generally occurs during the bond formation step 330. The thermal profileof the kiln is represented as profile 910 that is typically configuredby the kiln operation controls. Profile 910 describes the temperature ofthe interior of the kiln over time, represented as a heating ramp-upperiod, a hold period, and a cooling ramp-down region. A first exemplarythermal response 920 represents the internal temperature of the formedobject in the kiln during the curing step 280. In this example a poreformer having a combustion temperature T_(c1) where the rate upon whichthe temperature increases shows a rate change at line 940 to rapidlyreach the desired bond formation temperature Tb represented as line 950without exceeding the devitrification temperature Td 930 of the fiber.The completion of the combustion of the pore former results in adecrease in temperature toward the kiln temperature 910. Similarly, asecond exemplary thermal response 915 represents the internaltemperature of the formed object in the kiln during the curing step 280.In this example a second pore former having a combustion temperatureT_(c2) that is lower than the combustion temperature of the first poreformer T_(c1). In this second example, the internal temperature of theformed object increases rapidly at the combustion temperature T_(c2) atline 945 to quickly reach the desired bond formation temperature 950.Upon completion of the combustion of the pore former, the temperaturedecreases toward the kiln temperature 910.

In this embodiment, the kiln temperature profile 910 is set inaccordance with the characteristics and relative quantity of the poreformer so that the combustion temperature is reached and that thecombustion is completed so that the maximum temperature and duration attemperature is controlled relative to the devitrification temperature ofthe fiber. Because of the ability to quickly heat and cool the formedobject during the curing step 280, the amount of crystallization isminimized, either by avoiding exceeding the devitrification temperature,or by minimizing the duration of time the object exceeds thedevitrification temperature. The temperature excursions are bettercontrolled due to the combustion of the pore former since the heatingeffect is uniformly distributed throughout the object. The method avoidsthe inherent latency of convention and/or radiant heat transfer from thekiln or oven.

Additional control over the curing step 280 by controlling theenvironment of the kiln. For example, inert or stagnant air in the kilnor oven environment can delay the point at which the volatile components285 are removed. Furthermore, the pore former removal step 340 can befurther controlled by the environment by purging with an inert gas, suchas nitrogen, until the temperature is greater than the combustiontemperature of the pore former, and nearly that of the desired bondformation temperature. Oxygen is introduced at the high temperature, sothat when the pore former oxidizes, the temperature of the non-volatilematerials can be locally increased at or above the glass transitiontemperature, or the bond formation temperature, until the pore former isfully combusted. At that point, the temperature can be reduced to avoiddevitrification and/or the growth of grain boundaries of and within theresulting structure.

In yet another embodiment of the invention, the curing step 280 can beperformed using a primary heat source, such as a kiln or oven, with asecondary heat source supplementing the kiln or oven to rapidly anduniformly heat the object to the desired temperature for the bondformation step to control the degree of crystallinity that would occuras a function of time and temperature. In this embodiment, a flame heatsource can be applied directly to the object while it is in the kiln oroven.

The bonds formed between overlapping and adjacent nodes of theintertangled fibers forming the three-dimensional matrix 110 can beglass bonds having a composition substantially the same as thecomposition of the bulk fibers 210. The bonds can also be the result ofa reaction between the bulk fibers 210 and the bonding agent 220 to forma glass bond having a composition that is substantially different thanthe composition of the bulk fiber 210. Due to the regulatoryrequirements relating to the approval of materials for use as a medicaldevice or implant, it may be desirable to use approved materialcompositions as raw materials that are not significantly altered by thedevice fabrication methods and processes. Alternatively, it may bedesirable to use raw materials that are precursors to an approvedmaterial composition, that form the desired composition during thedevice fabrication methods and processes. The present invention providesa bioactive and resorbable tissue scaffold device that can be eitherfabricated using a variety of medically approved materials, orfabricated into a medically-approved material composition.

In an embodiment of the present invention, the strength and durabilityof the resorbable tissue scaffold can be enhanced by annealing theformed object subsequent to or during the curing step 280. During thebond formation step 330 when the non-volatile components 275 are heatedto the bond formation temperature and subsequently cooled, thermalgradients within the materials may occur during a subsequent coolingphase. Thermal gradients in the material during cooling may induceinternal stress that pre-loads the structure with stress thateffectively reduces the amount of external stress the object can endurebefore mechanical failure. Annealing the resorbable tissue scaffoldinvolves heating the object to a temperature that is the stress reliefpoint of the material, i.e., a temperature at which the glass materialis still hard enough to maintain its shape and form, but enough for anyinternal stress to be relieved. The annealing temperature is determinedby the composition of the resulting structure (i.e., the temperature atwhich the viscosity of the material softens to stress relief point), andthe duration of the annealing process is determined by the relative sizeand thickness of the internal structure (i.e. the time at which thetemperature reaches steady state throughout the object). The annealingprocess cools slowly at a rate that is limited by the heat capacity,thermal conductivity, and thermal expansion coefficient of the material.In an exemplary embodiment of the present invention, a fourteenmillimeter diameter extruded cylinder of a porous resorbable tissuescaffold having a 13-93 composition can be annealed by heating theobject in a kiln or oven at 500° C. for six hours and cooled to roomtemperature over approximately four hours.

The resorbable tissue scaffolds of the present invention can be used inprocedures such as an osteotomy (for example in the hip, knee, hand andjaw), a repair of a structural failure of a spine (for example, anintervertebral prosthesis, lamina prosthesis, sacrum prosthesis,vertebral body prosthesis and facet prosthesis), a bone defect filler,fracture revision surgery, tumor resection surgery, hip and kneeprostheses, bone augmentation, dental extractions, long bonearthrodesis, ankle and foot arthrodesis, including subtalar implants,and fixation screws pins. The resorbable tissue scaffolds of the presentinvention can be used in the long bones, including, but not limited to,the ribs, the clavicle, the femur, tibia, and fibula of the leg, thehumerus, radius, and ulna of the arm, metacarpals and metatarsals of thehands and feet, and the phalanges of the fingers and toes. Theresorbable tissue scaffolds of the present invention can be used in theshort bones, including, but not limited to, the carpals and tarsals, thepatella, together with the other sesamoid bones. The resorbable tissuescaffolds of the present invention can be used in the other bones,including, but not limited to, the cranium, mandible, sternum, thevertebrae and the sacrum. In an embodiment, the tissue scaffolds of thepresent invention have high load bearing capabilities compared toconventional devices. In an embodiment, the tissue scaffolds of thepresent invention require less implanted material compared toconventional devices. Furthermore, the use of the tissue scaffold of thepresent invention requires less ancillary fixation due to the strengthof the material. In this way, the surgical procedures for implanting thedevice are less invasive, more easily performed, and do not requiresubsequent surgical procedures to remove instruments and ancillaryfixations.

In one specific application, a tissue scaffold of the present invention,fabricated as described above, can be used as a spinal implant 800 asdepicted in FIG. 8 and FIG. 9. Referring to FIG. 8 and FIG. 9, thespinal implant 800 includes a body 810 having a wall 820 sized forengagement within a space S between adjacent vertebrae V to maintain thespace S. The device 800 is formed from bioactive glass fibers that canbe formed into the desired shape using extrusion methods to form acylindrical shape that can be cut or machined into the desired size. Thewall 820 has a height h that corresponds to the height H of the space S.In one embodiment, the height h of the wall 820 is slightly larger thanthe height H of the intervertebral space S. The wall 820 is adjacent toand between a superior engaging surface 840 and an inferior engagingsurface 850 that are configured for engaging the adjacent vertebrae V asshown in FIG. 9.

In another specific application, a tissue scaffold of the presentinvention, fabricated as described above, can be used as an osteotomywedge implant 1000 as depicted in FIGS. 10 and 11. Referring to FIG. 10and FIG. 11, the osteotomy implant 1000 may be generally described as awedge designed to conform to an anatomical cross section of, forexample, a tibia, thereby providing mechanical support to a substantialportion of a tibial surface. The osteotomy implant is formed frombioactive glass fibers bonded and fused into a porous material that canbe formed from an extruded rectangular block, and cut or machined intothe contoured wedge shape in the desired size. The proximal aspect 1010of the implant 1000 is characterized by a curvilinear contour. Thedistal aspect 1020 conforms to the shape of a tibial bone in itsimplanted location. The thickness of the implant 1000 may vary fromabout five millimeters to about twenty millimeters depending on thepatient size and degree of deformity. Degree of angulation between thesuperior and inferior surfaces of the wedge may also be varied.

FIG. 11 illustrates one method for the use of the osteotomy wedgeimplant 1000 for realigning an abnormally angulated knee. A transverseincision is made into a medial aspect of a tibia while leaving a lateralportion of the tibia intact and aligning the upper portion 1050 and thelower portion 1040 of the tibia at a predetermined angle to create aspace 1030. The substantially wedge-shaped implant 1000 is inserted inthe space 1030 to stabilize portions of the tibia as it heals into thedesired position with the implant 1000 dissolving into the body asherein described. Fixation pins may be applied as necessary to stabilizethe tibia as the bone regenerates and heals the site of the implant.

Generally, the use of a resorbable bone tissue scaffold of the presentinvention as a bone graft involves surgical procedures that are similarto the use of autograft or allograft bone grafts. The bone graft canoften be performed as a single procedure if enough material is used tofill and stabilize the implant site. In an embodiment, fixation pins canbe inserted into the surrounding natural bone, and/or into and throughthe resorbable bone tissue scaffold. The resorbable bone tissue scaffoldis inserted into the site and fixed into position. The area is thenclosed up and after a certain healing and maturing period, the bone willregenerate and become solidly fused.

The use of a resorbable bone tissue scaffold of the present invention asa bone defect filler involves surgical procedures that can be performedas a single procedure, or multiple procedures in stages or phases ofrepair. In an embodiment, a resorbable tissue scaffold of the presentinvention is placed at the bone defect site, and attached to the boneusing fixation pins or screws. Alternatively, the resorbable tissuescaffold can be externally secured into place using braces. The area isthen closed up and after a certain healing and maturing period, the bonewill regenerate to repair the defect.

-   -   A method of filling a defect in a bone includes filling a space        in the bone with a resorbable tissue scaffold comprising        bioactive fibers bonded into a porous matrix, the porous matrix        having a pore size distribution to facilitate in-growth of bone        tissue; and attaching the resorbable tissue scaffold to the        bone.    -   A method of treating an osteotomy includes filling a space in        the bone with a resorbable tissue scaffold comprising bioactive        fibers bonded into a porous matrix, the porous matrix having a        pore size distribution to facilitate in-growth of bone tissue;        and attaching the resorbable tissue scaffold to the bone.    -   A method of treating a structural failure of a vertebrae        includes filling a space in the bone with a resorbable tissue        scaffold comprising bioactive fibers bonded into a porous        matrix, the porous matrix having a pore size distribution to        facilitate in-growth of bone tissue; and attaching the        resorbable tissue scaffold to the bone.    -   A method of fabricating a synthetic bone prosthesis includes        mixing bioactive fiber with a binder, a pore former and a liquid        to provide a plastically formable batch; kneading the formable        batch to distribute the bioactive fiber with the pore former and        the binder, the formable batch a homogeneous mass of        intertangled and overlapping bioactive fiber; forming the        formable batch into a desired shape to provide a shaped form;        drying the shaped form to remove the liquid; heating the shaped        form to remove the binder and the pore former; and heating the        shaped form to a bond formation temperature using a primary heat        source and a secondary heat source to form bonds between the        intertangled and overlapping bioactive glass fiber.    -   In an embodiment, the present invention discloses use of        bioactive fibers bonded into a porous matrix, the porous matrix        having a pore size distribution to facilitate in-growth of bone        tissue for the treatment of a bone defect.    -   In an embodiment, the present invention discloses use of        bioactive fibers bonded into a porous matrix, the porous matrix        having a pore size distribution to facilitate in-growth of bone        tissue for the treatment of an osteotomy.    -   In an embodiment, the present invention discloses use of        bioactive fibers bonded into a porous matrix, the porous matrix        having a pore size distribution to facilitate in-growth of bone        tissue for the treatment of a structural failure of various        parts of a spinal column.

EXAMPLES

The following examples are provided to further illustrate and tofacilitate the understanding of the disclosure. These specific examplesare intended to be illustrative of the disclosure and are not intendedto be limiting in an way.

In a first exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 75 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form, as the non-volatile components with 16 grams ofHPMC as an organic binder and 20 grams of PMMA with a particle size of25-30 μm as a pore former and approximately 40 grams of deionized water,adjusted as necessary to provide a plastically formable mixture. Themixture was extruded into a 14 mm diameter rod and dried in a microwavedryer. The volatile components were burned out in an air-purged oven andthen heat treated at 720° C. for one hour to bond and fuse the 13-93fiber into the bioresorbable tissue scaffold. The PMMA pore formerinitiates combustion at approximately 346° C. while the oven heats inorder to rapidly increase the internal temperature of the scaffold. Theporosity for this example was measured to be 69.4%.

In a second exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 5 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form, and 1 gram of 13-93 bioactive glass in a powderform (also from Mo-Sci Corporation) as the nonvolatile components with 2grams of HPMC as an organic binder and 5 grams of PMMA with a particlesize of 25-30 μm as a pore former and approximately 8 grams of deionizedwater, adjusted as necessary to provide a plastically formable mixture.The mixture was extruded into a 14 mm diameter rod, and dried in amicrowave dryer. The volatile components were burned out in anair-purged oven and heat treated at 690° C. for 45 minutes to bond andfuse the 13-93 fiber into the bioresorbable tissue scaffold using thebioactive glass material to coat the adjacent and overlapping fiber withglass. The PMMA pore former initiates combustion at approximately 346°C. while the oven heats in order to rapidly increase the internaltemperature of the scaffold. The porosity for this example was measuredto be 76%.

In a third exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 5 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form, and 2 grams of 13-93 bioactive glass in a powderform (also from Mo-Sci Corporation) as the nonvolatile components with 2grams of HPMC as an organic binder and 5 grams of 4015 graphite powderfrom Asbury Carbons, Asbury, N.J. with a distribution of particle sizesof between 150 to 425 μm as a pore former and approximately 10 grams ofdeionized water, adjusted as necessary to provide a plastically formablemixture. The mixture was extruded into a 14 mm diameter rod and driedfor 30 minutes at 125° C. The volatile components were burned out in anair-purged oven and heat treated at 800° C. for 45 minutes to bond andfuse the 13-93 fiber into the bioresorbable tissue scaffold using thebioactive glass material to coat the adjacent and overlapping fiber withglass. The graphite pore former initiates combustion at approximately603° C. while the oven heats in order to rapidly increase the internaltemperature of the scaffold. The porosity for this example was measuredto be 66.5% with a compressive strength of 7.0 MPa.

In a fourth exemplary embodiment a resorbable scaffold is formed from amixture of 45S5 fiber and 13-93 fiber by mixing 45 grams of 13-93 fiberhaving an average diameter of approximately 34 μm obtained from Mo-SciCorporation, Rolla, Mo. 65401, in bulk form with 30 grams of 45S5 fiberhaving an average diameter of 14 μm, (also from Mo-Sci Corporation) asthe nonvolatile components with 16 grams of HPMC as an organic binderand 20 grams of starch having an average particle size of 50 μm as apore former and approximately 40 grams of deionized water, adjusted asnecessary to provide a plastically formable mixture. The mixture wasextruded into a 14 mm diameter rod and dried in a microwave dryer. Thevolatile components were burned out in an air-purged oven and heattreated at 715° C. for 1 hour to bond and fuse the 13-93 and 45S5 fiberinto the bioresorbable tissue scaffold with glass material from thefibers coating the adjacent and overlapping fiber. The starch poreformer initiates combustion at approximately 292° C. while the ovenheats in order to rapidly increase the internal temperature of thescaffold. The porosity for this example was determined to be 40.4%

In a fifth exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 5 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form, and 2 grams of 13-93 bioactive glass in a powderform (also from Mo-Sci Corporation) as the nonvolatile components with 2grams of HPMC as an organic binder and 1.5 grams of PMMA with a particlesize of 100 μm as a pore former and approximately 7 grams of deionizedwater, adjusted as necessary to provide a plastically formable mixture.The mixture was extruded into a 14 mm diameter rod and dried in amicrowave dryer. The volatile components were burned out in anair-purged oven and heat treated at 680° C. for 45 minutes to bond andfuse the 13-93 fiber into the bioresorbable tissue scaffold using thebioactive glass material to coat the adjacent and overlapping fiber withglass. The PMMA pore former initiates combustion at approximately 346°C. while the oven heats in order to rapidly increase the internaltemperature of the scaffold. The porosity for this example was measuredto be 58.5% with a compressive strength of 4.7 MPa.

In a sixth exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 5 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form as the nonvolatile components with 2 grams of HPMCas an organic binder and 1.5 grams of PMMA with a particle size of 100μm as a pore former and approximately 8 grams of deionized water,adjusted as necessary to provide a plastically formable mixture. Themixture was extruded into a 14 mm diameter rod and dried in a microwavedryer. The volatile components were burned out in an air-purged oven andheat treated at 700° C. for 90 minutes to bond and fuse the 13-93 fiberinto the bioresorbable tissue scaffold using bioactive glass materialfrom the fiber to coat the adjacent and overlapping fiber with glass.The PMMA pore former initiates combustion at approximately 346° C. whilethe oven heats in order to rapidly increase the internal temperature ofthe scaffold. The porosity for this example was measured to be 47.0%with a compressive strength of 22.5 MPa.

In a seventh exemplary embodiment a resorbable scaffold is formed from13-93 fiber by mixing 5 grams of 13-93 fiber having an average diameterof approximately 34 μm obtained from Mo-Sci Corporation, Rolla, Mo.65401, in bulk form, and 3 grams of 13-93 bioactive glass in a powderform (also from Mo-Sci Corporation) as the nonvolatile components with 2grams of HPMC as an organic binder and 5 grams of PMMA with a particlesize of 25-30 μm as a pore former and approximately 8 grams of deionizedwater, adjusted as necessary to provide a plastically formable mixture.The mixture was extruded into a 14 mm diameter rod and dried in amicrowave dryer. The volatile components were burned out in anair-purged oven and heat treated at 710° C. for 45 minutes to bond andfuse the 13-93 fiber into the bioresorbable tissue scaffold using thebioactive glass material to coat the adjacent and overlapping fiber withglass. The PMMA pore former initiates combustion at approximately 346°C. while the oven heats in order to rapidly increase the internaltemperature of the scaffold. The porosity for this example was measuredto be 50.2% with a compressive strength of 20.1 MPa.

The present invention has been herein described in detail with respectto certain illustrative and specific embodiments thereof, and it shouldnot be considered limited to such, as numerous modifications arepossible without departing from the spirit and scope of the appendedclaims.

What is claimed is:
 1. A spinal implant comprising: a body having aheight sized for engagement within a space between adjacent vertebrae;the body having a composition that is formed essentially of bioactiveglass fibers sintered into a rigid, porous structure having a porosityof 40% to 85%, the porosity having a controlled pore size and acontrolled pore size distribution established from a pore former tooptimize pore morphology to enhance flow of blood and body fluid withinthe rigid, porous structure; and the body adapted to be inserted intothe space between adjacent vertebrae wherein body facilitates aningrowth of tissue to promote fusion and wherein the body is resorbable.2. The spinal implant according to claim 1 wherein the height is greaterthan the space between adjacent vertebrae.
 3. The spinal implantaccording to claim 1 wherein the bioactive glass fibers include acrystalline phase.
 4. The spinal implant according to claim 1 whereinthe bioactive glass fibers have a composition comprising mol %quantities of 6% Na2O; 7.9% K2O; 7.7% MgO; 22.1% CaO; 1.7% P2O5; and54.6% SiO2.
 5. The spinal implant according to claim 1 wherein the bodyhas a porosity that is less than 50% and a compressive strength that isgreater than 22 MPa.
 6. The spinal implant according to claim 1 whereinthe bioactive glass fibers have a plurality of compositions.
 7. Thespinal implant according to claim 1 wherein the porous structure furthercomprises bioactive glass coating the bioactive glass fibers.